Implantable Device Having a Slow Dissolving Polymer

ABSTRACT

The present invention provides an implantable device having a coating including a slow dissolving polymer or material and the methods of making and using the same.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of co-pending U.S. application Ser.No. 11/933,017, filed on Oct. 31, 2007, and published as United StatesPatent Application Publication number 2009-0110711 A1, on Apr. 30, 2009,which is incorporated by reference herein in its entirety, including anydrawings, and is incorporated by reference herein for all purposes.

FIELD OF THE INVENTION

The present invention relates to a medical device having a dissolvablecoating.

BACKGROUND OF THE INVENTION

An ongoing goal of biomaterials research is the improvement ofcompositions from which medical articles, such as medical devices andcoatings for medical devices, are produced. An example of such a medicalarticle is an implantable medical device.

In a variety of medical procedures such as, for example, percutaneoustransluminal coronary angioplasty (PTCA), stents play an important role.Stents act as a mechanical intervention to physically hold open and, ifdesired, expand a passageway within a subject. However, thrombosis andrestenosis, which may develop several months after a particularprocedure, are among the problems associated with the use of stents andcan create a need for additional angioplasty or a surgical by-passoperation.

In order to address these problems, stents are being developed toprovide for the local delivery of agents. A method of local deliveryincludes coating the surface of a medical article, e.g., a stent, with apolymeric carrier and attaching an agent to, or blending it with, thepolymeric carrier. These agents can be used alone or in combination withother suitable agents. However, there is a continual need for novelpolymer coatings for use on drug delivery devices.

The embodiments described below address the above-identified needs andissues.

SUMMARY OF THE INVENTION

The present invention relates to an implantable device that includes adissolvable coating or polymeric matrix. Upon implantation, thephysiological environment in the implantation site can dissolve away thepolymeric matrix via, for example, degradation of the polymer. In someembodiments, the dissolvable coating comprises apoly(D,L-lactide-co-glycolide-b-ethyleneglycol-b-D,L-lactide-co-glycolide) triblock copolymer (PLGA-PEG-PLGA)with D,L-lactide/glycolide molar ratio ranging from 5/1 to 3/2 and molarconcentration of PEG ranging from 5 to 40 percent.

As used herein, a material that is described as a layer “disposed over”an indicated substrate, e.g., a stent or another layer, refers to arelatively thin coating of the material applied directly to essentiallythe entire exposed surface of the indicated substrate. The term“disposed over” may, however, also refer to the application of the thinlayer of material to an intervening layer that has been applied to thesubstrate, wherein the material is applied in such a manner that, werethe intervening layer not present, the material would coversubstantially the entire exposed surface of the substrate. As usedherein, the term “polymeric matrix” is used interchangeably with theterm “polymeric coating” or “coating.”

In some embodiments, the polymeric matrix can include any non-degradableor biodurable polymer or material.

In some embodiments, the polymeric matrix can include a bioactive agentsuch as a therapeutic substance or drug. Some examples of the bioactiveagent include siRNA and/or other oligoneucleotides that inhibitendothelial cell migration. The bioactive agent can also belysophosphatidic acid (LPA) or sphingosine-1-phosphate (S1P). LPA is a“bioactive” phospholipid able to generate growth factor-like activitiesin a wide variety of normal and malignant cell types. LPA plays animportant role in normal physiological processes such as wound healing,and in vascular tone, vascular integrity, or reproduction. Some otherexemplary bioactive agents are paclitaxel, docetaxel, estradiol,17-beta-estradiol, nitric oxide donors, super oxide dismutases, superoxide dismutases mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO), biolimus, tacrolimus, dexamethasone, rapamycin,rapamycin derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), γ-hiridun, clobetasol,pimecrolimus, imatinib mesylate, midostaurin, prodrugs thereof, co-drugsthereof, and combinations thereof.

The polymeric matrix or coating can be formed on an implantable devicesuch as a stent, which can be implanted in a patient to treat, prevent,mitigate, or reduce a vascular medical condition, or to provide apro-healing effect. Examples of these conditions includeatherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissectionor perforation, vascular aneurysm, vulnerable plaque, chronic totalocclusion, claudication, anastomotic proliferation (for vein andartificial grafts), bile duct obstruction, ureter obstruction, tumorobstruction, or combinations of these.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1C are scanning electronic microscopic (SEM) images of coatingsformed of polymers of invention PLGA-PEG-PLGA having poly(ethyleneglycol) (PEG) in different molecular weights and ratios;

FIG. 2 shows the release profile of everolimus from coatings formed ofpolymers of invention having PEG in different molecular weights andratios;

FIG. 3 shows swelling test results of coatings formed of polymers ofinvention having PEG in different molecular weights and ratios.

DETAILED DESCRIPTION

The present invention relates to an implantable device that includes adissolvable coating or polymeric matrix. Upon implantation, thephysiological environment in the implantation site can dissolve away thepolymeric matrix via, for example, degradation of the polymer. In someembodiments, the dissolvable coating comprises apoly(D,L-lactide-co-glycolide-b-ethyleneglycol-b-D,L-lactide-co-glycolide) triblock copolymer (PLGA-PEG-PLGA)with D,L-lactide/glycolide molar ratio ranging from 5/1 to 3/2 and molarconcentration of PEG ranging from 5 to 40 percent.

As used herein, a material that is described as a layer “disposed over”an indicated substrate, e.g., a stent or another layer, refers to arelatively thin coating of the material applied directly to essentiallythe entire exposed surface of the indicated substrate. The term“disposed over” may, however, also refer to the application of the thinlayer of material to an intervening layer that has been applied to thesubstrate, wherein the material is applied in such a manner that, werethe intervening layer not present, the material would coversubstantially the entire exposed surface of the substrate. As usedherein, the term “polymeric matrix” is used interchangeably with theterm “polymeric coating” or “coating.”

In some embodiments, the polymeric matrix can include any non-degradableor biodurable polymer or material.

In some embodiments, the polymeric matrix can include a bioactive agentsuch as a therapeutic substance or drug. Some examples of the bioactiveagent include siRNA and/or other oligoneucleotides that inhibitendothelial cell migration. The bioactive agent can also belysophosphatidic acid (LPA) or sphingosine-1-phosphate (SIP). LPA is a“bioactive” phospholipid able to generate growth factor-like activitiesin a wide variety of normal and malignant cell types. LPA plays animportant role in normal physiological processes such as wound healing,and in vascular tone, vascular integrity, or reproduction. Some otherexemplary bioactive agents are paclitaxel, docetaxel, estradiol,17-beta-estradiol, nitric oxide donors, super oxide dismutases, superoxide dismutases mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO), biolimus, tacrolimus, dexamethasone, rapamycin,rapamycin derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), γ-hiridun, clobetasol,pimecrolimus, imatinib mesylate, midostaurin, prodrugs thereof, co-drugsthereof, and combinations thereof.

The polymeric matrix or coating can be formed on an implantable devicesuch as a stent, which can be implanted in a patient to treat, prevent,mitigate, or reduce a vascular medical condition, or to provide apro-healing effect. Examples of these conditions includeatherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissectionor perforation, vascular aneurysm, vulnerable plaque, chronic totalocclusion, claudication, anastomotic proliferation (for vein andartificial grafts), bile duct obstruction, ureter obstruction, tumorobstruction, or combinations of these.

DEFINITIONS

Wherever applicable, the definitions to some terms used throughout thedescription of the present invention as provided below shall apply.

As used herein, the term “biostable” is used interchangeably with theterm “biodurable”. A biostable polymer or coating refers to a polymer orcoating that is not biodegradable, which is defined blow.The terms “biologically degradable” (or “biodegradable”), “biologicallyerodable” (or “bioerodable”), “biologically absorbable” (or“bioabsorbable”), and “biologically resorbable” (or “bioresorbable”), inreference to polymers and coatings, are used interchangeably and referto polymers and coatings that are capable of being completely orsubstantially completely degraded, dissolved, and/or eroded over timewhen exposed to physiological conditions and can be gradually resorbed,absorbed and/or eliminated by the body, or that can be degraded intofragments that can pass through the kidney membrane of an animal (e.g.,a human), e.g., fragments having a molecular weight of about 40,000Daltons (40 kDa) or less. The process of breaking down and eventualabsorption and elimination of the polymer or coating can be caused by,e.g., hydrolysis, metabolic processes, oxidation, enzymatic processes,bulk or surface erosion, and the like. Whenever the reference is made to“biologically degradable,” “biologically erodable,” “biologicallyabsorbable,” and “biologically resorbable” stent coatings or polymersforming such stent coatings, it is understood that after the process ofdegradation, erosion, absorption, and/or resorption has been completedor substantially completed, no coating or substantially little coatingwill remain on the stent. Whenever the terms “degradable,”“biodegradable,” or “biologically degradable” are used in thisapplication, they are intended to broadly include biologicallydegradable, biologically erodable, biologically absorbable, andbiologically resorbable polymers or coatings.

“Physiological conditions” refer to conditions to which an implant isexposed within the body of an animal (e.g., a human). Physiologicalconditions include, but are not limited to, “normal” body temperaturefor that species of animal (approximately 37° C. for a human) and anaqueous environment of physiologic ionic strength, pH and enzymes. Insome cases, the body temperature of a particular animal may be above orbelow what would be considered “normal” body temperature for thatspecies of animal. For example, the body temperature of a human may beabove or below approximately 37° C. in certain cases. The scope of thepresent invention encompasses such cases where the physiologicalconditions (e.g., body temperature) of an animal are not considered“normal.”

A “prohealing” drug or agent, in the context of a blood-contactingimplantable device, refers to a drug or agent that has the property thatit promotes or enhances re-endothelialization of arterial lumen topromote healing of the vascular tissue. The portion(s) of an implantabledevice (e.g., a stent) containing a prohealing drug or agent canattract, bind and eventually become encapsulated by endothelial cells(e.g., endothelial progenitor cells). The attraction, binding, andencapsulation of the cells will reduce or prevent the formation ofemboli or thrombi due to the loss of the mechanical properties thatcould occur if the stent was insufficiently encapsulated. The enhancedre-endothelialization can promote the endothelialization at a ratefaster than the loss of mechanical properties of the stent.

The prohealing drug or agent can be dispersed in the body of thebioabsorbable polymer substrate or scaffolding. The prohealing drug oragent can also be dispersed within a bioabsorbable polymer coating overa surface of an implantable device (e.g., a stent).

“Endothelial progenitor cells” refer to primitive cells made in the bonemarrow that can enter the bloodstream and go to areas of blood vesselinjury to help repair the damage. Endothelial progenitor cells circulatein adult human peripheral blood and are mobilized from bone marrow bycytokines, growth factors, and ischemic conditions. Vascular injury isrepaired by both angiogenesis and vasculogenesis mechanisms. Circulatingendothelial progenitor cells contribute to repair of injured bloodvessels mainly via a vasculogenesis mechanism.

As used herein, a “co-drug” is a drug that is administered concurrentlyor sequentially with another drug to achieve a particularpharmacological effect. The effect may be general or specific. Theco-drug may exert an effect different from that of the other drug, or itmay promote, enhance or potentiate the effect of the other drug.As used herein, the term “prodrug” refers to an agent rendered lessactive by a chemical or biological moiety, which metabolizes into orundergoes in vivo hydrolysis to form a drug or an active ingredientthereof. The term “prodrug” can be used interchangeably with terms suchas “proagent”, “latentiated drugs”, “bioreversible derivatives”, and“congeners”. N. J. Harper, Drug latentiation, Prog Drug Res., 4: 221-294(1962); E. B. Roche, Design of Biopharmaceutical Properties throughProdrugs and Analogs, Washington, D.C.: American PharmaceuticalAssociation (1977); A. A. Sinkula and S. H. Yalkowsky, Rationale fordesign of biologically reversible drug derivatives: prodrugs, J. Pharm.Sci., 64: 181-210 (1975). Use of the term “prodrug” usually implies acovalent link between a drug and a chemical moiety, though some authorsalso use it to characterize some forms of salts of the active drugmolecule. Although there is no strict universal definition of a prodrugitself, and the definition may vary from author to author, prodrugs cangenerally be defined as pharmacologically less active chemicalderivatives that can be converted in vivo, enzymatically ornonenzymatically, to the active, or more active, drug molecules thatexert a therapeutic, prophylactic or diagnostic effect. Sinkula andYalkowsky, above; V. J. Stella et al., Prodrugs: Do they have advantagesin clinical practice?, Drugs, 29: 455-473 (1985).The terms “polymer” and “polymeric” refer to compounds that are theproduct of a polymerization reaction. These terms are inclusive ofhomopolymers (i.e., polymers obtained by polymerizing one type ofmonomer), copolymers (i.e., polymers obtained by polymerizing two ormore different types of monomers), terpolymers, etc., including random,alternating, block, graft, dendritic, crosslinked and any othervariations thereof.As used herein, the term “implantable” refers to the attribute of beingimplantable in a mammal (e.g., a human being or patient) that meets themechanical, physical, chemical, biological, and pharmacologicalrequirements of a device provided by laws and regulations of agovernmental agency (e.g., the U.S. FDA) such that the device is safeand effective for use as indicated by the device. As used herein, an“implantable device” may be any suitable substrate that can be implantedin a human or non-human animal. Examples of implantable devices include,but are not limited to, self-expandable stents, balloon-expandablestents, coronary stents, peripheral stents, stent-grafts, catheters,other expandable tubular devices for various bodily lumen or orifices,grafts, vascular grafts, arterio-venous grafts, by-pass grafts,pacemakers and defibrillators, leads and electrodes for the preceding,artificial heart valves, anastomotic clips, arterial closure devices,patent foramen ovale closure devices, cerebrospinal fluid shunts, andparticles (e.g., drug-eluting particles, microparticles andnanoparticles). The stents may be intended for any vessel in the body,including neurological, carotid, vein graft, coronary, aortic, renal,iliac, femoral, popliteal vasculature, and urethral passages.As used herein, the term “implantable device” is used interchangeablywith the term “medical device.”An implantable device can be designed for the localized delivery of atherapeutic agent. A medicated implantable device may be constructed inpart, e.g., by coating the device with a coating material containing atherapeutic agent. The body of the device may also contain a therapeuticagent.

An implantable device can be fabricated with a coating containingpartially or completely a biodegradable/bioabsorbable/bioerodablepolymer, a biostable polymer, or a combination thereof. An implantabledevice itself can also be fabricated partially or completely from abiodegradable/bioabsorbable/bioerodable polymer, a biostable polymer, ora combination thereof.

As used herein, a material that is described as a layer or a film (e.g.,a coating) “disposed over” an indicated substrate (e.g., an implantabledevice) refers to, e.g., a coating of the material disposed directly orindirectly over at least a portion of the surface of the substrate.Direct depositing means that the coating is applied directly to theexposed surface of the substrate. Indirect depositing means that thecoating is applied to an intervening layer that has been disposeddirectly or indirectly over the substrate. In some embodiments, the terma “layer” or a “film” excludes a film or a layer formed on anon-implantable device.In the context of a stent, “delivery” refers to introducing andtransporting the stent through a bodily lumen to a region, such as alesion, in a vessel that requires treatment. “Deployment” corresponds tothe expanding of the stent within the lumen at the treatment region.Delivery and deployment of a stent are accomplished by positioning thestent about one end of a catheter, inserting the end of the catheterthrough the skin into a bodily lumen, advancing the catheter in thebodily lumen to a desired treatment location, expanding the stent at thetreatment location, and removing the catheter from the lumen.

Dissolvable Coating

As used herein, wherein the term “water dissolvable” refers to theattribute of being water soluble of a material or polymer described inthis application. This term also encompasses the attribute of a materialbecoming water soluble if the water includes an ion, which can be ananion or cation.

Examples of such ions are, but not limited to, ions present in aphysiological environment, e.g., Na⁺, K⁺, Ca⁺², Mg⁺², Al⁺³, Cl⁻, SO₄ ⁻²,or phosphate ions. The term “soluble” refers to the attribute of amaterial capable of forming a solution having a concentration of thematerial at least 1 g per 100 cc (or mL) of water at ambient temperature(20° C.).

As used herein, the term “slow dissolving” refers to the attribute of apolymer or material that will not completely dissolve in water or aphysiological environment upon contact with water or the physiologicalenvironment but rather, will dissolve into a physiological environmentover an extended period of time, e.g., one day to up to two years, e.g.,a period from about 2 days to about 2 years, from about 4 days to about20 months, from about 7 days to about 18 months, from about 14 days toabout 16 months, from about 30 days to about 14 months, from about 2months to about 12 months, or about 6 months. In some embodiments, theterm “slow dissolving” can be the attribute of a polymeric matrixcapable of being dissolved 50 mass % (half life) over a period up toabout two years, about one year, about 6 months, about 3 moths, about 2months, about one months, about 2 weeks, about 1 week, about 2 days, orabout 1 day.

In some embodiments, the coating can include a PLGA-PEG-PLGA triblockcopolymer. As used herein, the term PLGA is poly(D,L-lacticacid-co-glycolic acid), and PEG is poly(ethylene glycol).

In the PLGA-PEG-PLGA triblock copolymer, the PEG blocks dissolve quicklyin an aqueous environment such as a physiological environment andtherefore impart dissolvability to the polymer. In addition, the PLGAblocks impart hydrophobicity to the polymer, and the PEG block impartshydrophilicity to the polymer. Therefore, by varying the concentrationof the PEG in the triblock copolymer, one can make a PLGA-PEG-PLGA blockpolymer having an optimal dissolution rate.

In some embodiments, the PLGA-PEG-PLGA triblock copolymer can be formedof PLGA and PEG blocks with varying molecular weights. Generally, thePEG block can have a weight average molecular weight (M_(w)) below about40 KD. In some embodiments, the PEG block can have a M_(w) from about300 D to about 40 KD. For example, the PEG block can have a M_(w) ofabout 500 D, about 1 KD, about 2 KD, about 5 KD, about 8 KD, about 10KD, about 15 KD, about 20 KD, about 30 KD, about 35 KD, or about 40 KD.As used herein the term “about” refers to a variation within 10% of theindicated value. The PLGA block can have a M_(w) from about 5 KD toabout 100 KD, depending on the desired rate of dissolution. In selectinga proper range of molecular weight for the PLGA block, the followingfactors are to be considered, among other factors: (1) lactide (LA)units are generally hydrophobic and thus an increase in the percentageof LA units can decrease the water-uptake capacity of the polymer so asto decrease the dissolution rate of the polymer; (2) an increase of thepercentage of the PEG block in the polymer will generally increase thewater-uptake capacity of the polymer so as to increase the dissolutionrate of the polymer; and (3) glycolide (GA) units provide a degradationrate faster than lactide units. In some embodiments, the polymer canhave from about 10% to about 90% w/w of the PLGA blocks. In someembodiments, the polymer can have about 20%, about 40%, about 50%, about60%, about 70%, about 80% or about 90% by weight PLGA blocks. In someembodiments, the polymer can have about 30% by weight the GA units orconcentration.

The LA/GA ratio within a PLGA block can also vary. For example, theLA/GA ratio can be from about 5/95, about 10/90, about 20/80, about30/70, about 40/60, about 50/50, about 60/40, about 70/30, about 80/20,about 90/10, or about 95/5 w/w. Because the difference of rate ofdissolution in LA and GA units, a higher ratio of GA in the PLGA willgenerally generate a PLGA-PEG-PLGA block copolymer with a higher rate ofdissolution.

The LA units can be formed of a L-lactic acid (LLA), D-lactic acid(DLA), D,L-lactic acid (DLLA), or meso-lactic acid (mLA). If the LAunits are from LLA or DLA, then the PLGA-PEG-PLGA triblock copolymer canbe a semi-crystalline polymer. If the LA units are from DLLA, then thePLGA-PEG-PLGA triblock copolymer can be an amorphous polymer. Generally,an amorphous PLGA-PEG-PLGA block copolymer can have a higher dissolutionrate, and when used from controlled release of a drug by forming acoating including the drug, the coating can have a release profile ofthe drug that may include a burst release in the profile. The burstrelease can be controlled by using a semi-crystalline polymer. Asemi-crystalline PLGA-PEG-PLGA triblock copolymer can also have a slowerrate of dissolution compared with the amorphous polymer having the samecomposition.

The PLGA-PEG-PLGA tripolymer, can have an overall molecular weight(M_(w)) from about 40 KD to about 1000 KD. In some embodiments, thepolymer can have an overall M_(w) from about 50 KD to about 500 KD,e.g., about 60 KD, about 70 KD, about 80 KD, about 90 KD, about 100 KD,about 120 KD, about 130 KD, about 140 KD, about 150 KD, about 160 KD,about 170 KD, about 180 KD, about 190 KD, about 200 KD, about 250 KD,about 300 KD, about 350 KD, about 400 KD, or about 450 KD.

In some embodiments, the polymeric matrix or coating can include anatural polymer such as chitosan, alginate, fibrin, fibrinogen,cellulose, starch, dextran, dextrin, fragments and derivatives ofhyaluronic acid, heparin, fragments and derivatives of heparin,glycosamino glycan (GAG), GAG derivatives, polysaccharide, chitosan,alginate, or combinations thereof.

The coating described herein can be disposed over a substrate that canbe the surface of a medical device (e.g., the metallic surface of stent)or a biostable polymeric substrate. The biostable polymeric substratecan include a biostable polymer or material. Such biostable polymericsubstrate can include any biostable polymer.

Some examples of such biostable polymers include, but are not limitedto, polyesters, co-polyesters, polyethers, polyolefins, polyisobutyleneand ethylene-alphaolefin copolymers, acrylic polymers and copolymers,vinyl halide polymers and copolymers, such as polyvinyl chloride,polyvinyl ethers, such as polyvinyl methyl ether, polyvinylidenehalides, such as polyvinylidene chloride, polyvinyl ketones, polyvinylaromatics, such as polystyrene, polyvinyl alcohol (PVOH), polyvinylesters such a polyvinyl acetate (EVAL), copolymers of vinyl monomerswith each other and olefins, such as ethylene-methyl methacrylatecopolymers, acrylonitrile-styrene copolymers, ABS resins, andethylene-vinyl acetate copolymers, polyamides, such as Nylon 66 andpolycaprolactam, alkyd resins, co-polyamides, such as poly ether orester block amide (Pebax), polyoxymethylenes, polyimides, poly(propylenefumarate), poly(n-butyl methacrylate), poly(sec-butyl methacrylate),poly(isobutyl methacrylate), poly(tert-butyl methacrylate),poly(n-propyl methacrylate), poly(isopropyl methacrylate), poly(ethylmethacrylate), poly(methyl methacrylate), epoxy resins, polyurethanes,rayon, rayon-triacetate, cellulose acetate, cellulose butyrate,cellulose acetate butyrate, cellophane, cellulose nitrate, cellulosepropionate, cellulose ethers, carboxymethyl cellulose, polyethers suchas poly(ethylene glycol) (PEG), polyalkylene oxides such aspoly(ethylene oxide), poly(propylene oxide), polymers and co-polymers ofcholine or phosphoryl choline bearing monomers, polymers and co-polymersof hydroxyl bearing monomers, such as 2-hydroxyethyl methacrylate(HEMA), hydroxypropyl methacrylate (HPMA), hydroxypropyl methacrylamide,PEG acrylate (PEGA), PEG methacrylate,2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinyl pyrrolidone(VP), carboxylic acid bearing monomers such as methacrylic acid (MA),acrylic acid (AA), alkoxymethacrylate, alkoxyacrylate, and3-trimethylsilylpropyl methacrylate (TMSPMA),poly(styrene-isoprene-styrene)-PEG (SIS-PEG), polystyrene-PEG,polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG,poly(methyl methacrylate)-PEG (PMMA-PEG), polydimethylsiloxane-co-PEG(PDMS-PEG), PLURONICTM surfactants (polypropylene oxide-co-polyethyleneglycol), poly(tetramethylene glycol), hydroxy functional poly(vinylpyrrolidone), or combinations thereof. In some embodiments, thebiostable polymer is a polymer or copolymer from fluoro-olefins. Someexamples of such polymers are Solef™ polymers, such as poly(vinylidenefluoride) (PVDF) or poly(vinylidene fluoride-co-hexafluoropropene)(PVDF-HFP).

In some embodiments, the copolymer described herein can exclude any oneor more of the aforementioned polymers.

Bioactive Agents

These bioactive agents can be any agent which is a therapeutic,prophylactic, or diagnostic agent. These agents can haveanti-proliferative or anti-inflammmatory properties or can have otherproperties such as antineoplastic, antiplatelet, anti-coagulant,anti-fibrin, antithrombonic, antimitotic, antibiotic, antiallergic, orantioxidant properties.

These agents can be cystostatic agents, agents that promote the healingof the endothelium (other than by releasing or generating NO), or agentsthat promote the attachment, migration and proliferation of endothelialcells while quenching smooth muscle cell proliferation. Examples ofsuitable therapeutic and prophylactic agents include synthetic inorganicand organic compounds, proteins and peptides, polysaccharides and othersugars, lipids, and DNA and RNA nucleic acid sequences havingtherapeutic, prophylactic or diagnostic activities. Nucleic acidsequences include genes, antisense molecules, which bind tocomplementary DNA to inhibit transcription, and ribozymes. Some otherexamples of bioactive agents include antibodies, receptor ligands,enzymes, adhesion peptides, blood clotting factors, inhibitors or clotdissolving agents, such as streptokinase and tissue plasminogenactivator, antigens for immunization, hormones and growth factors,oligonucleotides such as antisense oligonucleotides and ribozymes andretroviral vectors for use in gene therapy. Examples ofanti-proliferative agents include rapamycin and its functional orstructural derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),and its functional or structural derivatives, paclitaxel and itsfunctional and structural derivatives. Examples of rapamycin derivativesinclude ABT-578, 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.Examples of paclitaxel derivatives include docetaxel. Examples ofantineoplastics and/or antimitotics include methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g.Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples ofsuch antiplatelets, anticoagulants, antifibrin, and antithrombinsinclude sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, thrombin inhibitorssuch as Angiomax (Biogen, Inc., Cambridge, Mass.), calcium channelblockers (such as nifedipine), colchicine, fibroblast growth factor(FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists,lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol loweringdrug, brand name Mevacor® from Merck & Co., Inc., Whitehouse Station,N.J.), monoclonal antibodies (such as those specific forPlatelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), super oxide dismutases, superoxide dismutase mimetic, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO), estradiol, anticancer agents, dietary supplements suchas various vitamins, and a combination thereof. Examples ofanti-inflammatory agents including steroidal and non-steroidalanti-inflammatory agents include biolimus, tacrolimus, dexamethasone,clobetasol, corticosteroids or combinations thereof. Examples of suchcytostatic substance include angiopeptin, angiotensin converting enzymeinhibitors such as captopril (e.g. Capoten® and Capozide® fromBristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril(e.g. Prinivil® and Prinzide® from Merck & Co., Inc., WhitehouseStation, N.J.). An example of an antiallergic agent is permirolastpotassium. Other therapeutic substances or agents which may beappropriate include alpha-interferon, pimecrolimus, imatinib mesylate,midostaurin, and genetically engineered epithelial cells. The foregoingsubstances can also be used in the form of prodrugs or co-drugs thereof.The foregoing substances also include metabolites thereof and/orprodrugs of the metabolites. The foregoing substances are listed by wayof example and are not meant to be limiting. Other active agents whichare currently available or that may be developed in the future areequally applicable.

In some embodiments, the bioactive agent that can be included in acoating described herein can specifically exclude any one or more of theabove identified drugs or agents.

The dosage or concentration of the bioactive agent required to produce afavorable therapeutic effect should be less than the level at which thebioactive agent produces toxic effects and greater than the level atwhich non-therapeutic results are obtained. The dosage or concentrationof the bioactive agent can depend upon factors such as the particularcircumstances of the patient, the nature of the trauma, the nature ofthe therapy desired, the time over which the ingredient administeredresides at the vascular site, and if other active agents are employed,the nature and type of the substance or combination of substances.Therapeutically effective dosages can be determined empirically, forexample by infusing vessels from suitable animal model systems and usingimmunohistochemical, fluorescent or electron microscopy methods todetect the agent and its effects, or by conducting suitable in vitrostudies. Standard pharmacological test procedures to determine dosagesare understood by those of ordinary skill in the art.

Examples of Implantable Device

As used herein, an implantable device can be any suitable medicalsubstrate that can be implanted in a human or veterinary patient.Examples of such implantable devices include self-expandable stents,balloon-expandable stents, stent-grafts, grafts (e.g., aortic grafts),heart valve prosthesis (e.g., artificial heart valves) or vasculargraft, cerebrospinal fluid shunts, pacemaker electrodes, catheters,endocardial leads (e.g., FINELINE and ENDOTAK, available from GuidantCorporation, Santa Clara, Calif.), and devices facilitating anastomosissuch as anastomotic connectors. The underlying structure of the devicecan be of virtually any design. The device can be made of a metallicmaterial or an alloy such as, but not limited to, cobalt chromium alloy(ELGILOY), stainless steel (316L), high nitrogen stainless steel, e.g.,BIODUR 108, cobalt chrome alloy L-605, “MP35N,” “MP20N,” ELASTINITE(Nitinol), tantalum, nickel-titanium alloy, platinum-iridium alloy,gold, magnesium, or combinations thereof. “MP35N” and “MP20N” are tradenames for alloys of cobalt, nickel, chromium and molybdenum availablefrom Standard Press Steel Co., Jenkintown, Pa. “MP35N” consists of 35%cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consistsof 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum. Devicesmade from bioabsorbable or biostable polymers could also be used withthe embodiments of the present invention. The device can be, forexample, a bioabsorbable stent.

Method of Use

The device (e.g., a stent) described herein is useful for a variety ofmedical procedures, including, by way of example, treatment ofobstructions caused by tumors in the bile ducts, esophagus,trachea/bronchi and other biological passageways. A stent having theabove-described coating is particularly useful for treating occludedregions of blood vessels caused by abnormal or inappropriate migrationand proliferation of smooth muscle cells, thrombosis, and restenosis.Stents may be placed in a wide array of blood vessels, both arteries andveins. Representative examples of sites include the iliac, renal, andcoronary arteries.

For implantation of a stent, an angiogram is first performed todetermine the appropriate positioning for stent therapy. An angiogram istypically accomplished by injecting a radiopaque contrasting agentthrough a catheter inserted into an artery or vein as an x-ray is taken.A guide wire is then advanced through the lesion or proposed site oftreatment. Over the guide wire is passed a delivery catheter that allowsa stent in its collapsed configuration to be inserted into thepassageway. The delivery catheter is inserted either percutaneously orby surgery into the femoral artery, brachial artery, femoral vein, orbrachial vein, and advanced into the appropriate blood vessel bysteering the catheter through the vascular system under fluoroscopicguidance. A stent having the above-described coating may then beexpanded at the desired area of treatment. A post-insertion angiogrammay also be utilized to confirm appropriate positioning.

EXAMPLES

The following examples are provided to illustrate the variousembodiments of the present invention described above and shall not beconstrued to limit the scope of the present invention.

Coatings formed of PDLGA-PEG-PDLGA with three different compositionswere subjected to simulated use tests followed by scanning electronicmicroscope (SEM) analysis, swelling tests, and drug release profileanalysis. The three compositions for the polymer are 70:30D,L-lactide/glycolide and 13%, 30%, and 40% PEG by mass.

FIG. 1A shows the SEM image of a coating formed of the above polymerwith a 10 kD PEG, 13% PEG by mass. FIG. 1B shows the SEM image of acoating formed of the above copolymer with a 20 kD PEG, 30% PEG by mass.FIG. 1C shows the SEM image of a coating formed of the above copolymerwith a 20 kD PEG, 40% PEG by mass. The coating formed of the abovecopolymer with 30% PEG by mass has good coating integrity, and so doesthe coating formed of the above copolymer with 40% PEG by mass. Thecoating formed of the above copolymer with 13% PEG by mass shows signsof cracking in high-stress areas, likely because of its relatively lowPEG content and relatively low total M_(w) (79,000 Daltons). There arealso signs of dissolution (surface erosion) in the block copolymer withthe 20 kD PEG block.

Drug release profile analysis after 1 and 3 days in porcine serum werealso conducted. The results are shown in FIG. 2. The coating formed ofthe polymers with the higher PEG content have burst releases with >99%of the drug released after one day. The coating formed of the polymerswith 13% PEG by mass also has a high initial release rate, but the drugrelease is more controlled than the two with a higher PEG content.

Swelling tests of the coatings formed of the above copolymers wereperformed on these polymers by creating thin films and immersing thosefilms in 37° C. phosphate buffer solution for certain periods of time.The swelling results are shown below in FIG. 3. The large amount ofswelling in the two materials with higher PEG contents explains theburst release for those two materials. Additionally, the films of the30% PEG and 40% PEG materials were soft and broke into small pieces atthe points where their graphs stop (the 40% PEG material broke after 2hours).

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. An implantable device comprising a coating deposited thereon, the coating comprising a PLGA-PEG-PLGA triblock copolymer; wherein PLGA in the PLGA-PEG-PLGA triblock copolymer is a block of poly(D,L-lactide-co-glycolide) and PEG in the PLGA-PEG-PLGA triblock copolymer is a block of poly(ethylene glycol); wherein the PLGA-PEG-PLGA triblock copolymer has a weight average molecular weight (Mw) from about 50 KD to about 200 KD and comprises: a molar ratio of D,L-lactide to glycolide of 5:1 to 3:2; and a content of PEG of about 30% or about 40% by weight; and wherein the PLGA-PEG-PLGA triblock copolymer breaks into fragments upon exposure of the coating to a physiological environment.
 2. The implantable device of claim 1, wherein the PLGA-PEG-PLGA triblock copolymer has a molecular weight of about 100 KD or above. 3-7. (canceled)
 8. The implantable device of claim 1, wherein the content of PEG in the PLGA-PEG-PLGA triblock copolymer is about 30% by weight.
 9. The implantable device of claim 1, wherein the content of PEG in the PLGA-PEG-PLGA triblock copolymer is about 40% by weight.
 10. The implantable device of claim 1, wherein the coating further comprises a bioactive agent.
 11. The implantable device of claim 10, wherein the bioactive agent is selected from the group consisting of paclitaxel, docetaxel, estradiol, 17-beta-estradiol, nitric oxide donors, super oxide dismutases, super oxide dismutases mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), biolimus, tacrolimus, dexamethasone, rapamycin, rapamycin derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, 40-epi-(N-1-tetrazolyl)-rapamycin (ABT-578), γ-hiridun, clobetasol, pimecrolimus, imatinib mesylate, midostaurin, feno fibrate, prodrugs thereof, co-drugs thereof, and combinations thereof.
 12. The implantable device of claim 1, which is a stent.
 13. The implantable device of claim 1, which is a bioabsorbable stent.
 14. A method comprising depositing a coating over an implantable device, the coating comprising a PLGA-PEG-PLGA triblock copolymer wherein PLGA in the PLGA-PEG-PLGA triblock copolymer is a block of poly(D,L-lactide-co-glycolide) and PEG in the PLGA-PEG-PLGA triblock copolymer is a block of poly(ethylene glycol); wherein the PLGA-PEG-PLGA triblock copolymer has a weight average molecular weight (Mw) from about 50 KD to about 200 KD and comprises: a molar ratio of D,L-lactide to glycolide of 5:1 to 3:2; and a content of PEG of about 30% or about 40% by weight; and wherein the PLGA-PEG-PLGA triblock copolymer breaks into fragments upon exposure of the coating to a physiological environment. 15-18. (canceled)
 19. The method of claim 16, wherein the content of PEG in the PLGA-PEG-PLGA triblock copolymer is about 30% by weight.
 20. The method of claim 14, wherein the content of PEG in the PLGA-PEG-PLGA triblock copolymer is about 40% by weight.
 21. The method of claim 14, which is a stent.
 22. The method of claim 14, which is a bioabsorbable stent.
 23. A method of treating a disorder in a patient, the method comprising implanting in the patient the stent according to claim 1, wherein the disorder is selected from the group consisting of atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection, vascular perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, patent foramen ovale, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.
 24. A method of treating a disorder in a patient, the method comprising implanting in the patient the stent according to claim 10, wherein the disorder is selected from the group consisting of atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection, vascular perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, patent foramen ovale, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.
 25. The implantable device of claim 10, wherein the bioactive agent is selected from the group consisting of paclitaxel, docetaxel, estradiol, 17-beta-estradiol, nitric oxide donors, super oxide dismutases, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), biolimus, tacrolimus, dexamethasone, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, 40-epi-(N-1-tetrazolyl)-rapamycin (ABT-578), γ-hiridun, clobetasol, pimecrolimus, imatinib mesylate, midostaurin, feno fibrate, and combinations thereof. 